Compositions and methods for treating cancer with anti-CD38 immunotherapy
Chimeric antigen receptors containing CD38 antigen binding domains are disclosed. Nucleic acids, recombinant expression vectors, host cells, antigen binding fragments, and pharmaceutical compositions, relating to the chimeric antigen receptors are also disclosed. Methods of treating or preventing cancer in a subject, and methods of making chimeric antigen receptor T cells are also disclosed.
1. A method of treating a hematological cancer in a human subject in need thereof, the method comprising administering to the human subject having the hematological cancer a pharmaceutical composition comprising an anti-tumor effective amount of a population of chimeric antigen receptor (CAR)-modified T cells,
wherein the CAR-modified T cells of the population each comprise a nucleic acid sequence that encodes a CAR comprising:
at least one extracellular antigen binding domain comprising a CD38 antigen binding domain comprising one of the amino acid sequences selected from the group consisting of the amino acid sequences of SEQ ID NO: 6, 8, 10, 22, and 24,at least one linker or spacer domain,at least one transmembrane domain, and at least one intracellular signaling domain,
wherein the nucleic acid sequence comprises a promoter operably linked to the CAR encoding sequence and the CAR has an amino acid sequence selected from the group consisting of SEQ ID NO: 90, 92, 94, 104, and 106, and wherein the CAR-modified T cells of the population are T cells of the human subject, thereby treating the hematological cancer of the human subject.
2. The method of claim 1 , wherein the at least one transmembrane domain comprises a transmembrane domain of a protein selected from the group consisting of the alpha chain of a T-cell receptor, the beta chain of a T-cell receptor, the zeta chain of a T-cell receptor, a CD8, a CD28, a CD3 epsilon, a CD45, a CD4, a CD5, a CD8, a CD9, a CD16, a CD22, a CD33, a CD37, a CD64, a CD80, a CD86, a CD134, a CD137 and a CD154.
3. The method of claim 2 , wherein the CD38 antigen binding domain, the at least one intracellular signaling domain, or both are connected to the at least one transmembrane domain by the at least one linker or spacer domain.
4. The method of claim 3 , wherein the at least one linker or spacer domain is obtained from the extracellular domain of CD8, TNFRSF19, or CD28, and is linked to the at least one transmembrane domain.
5. The method of claim 1 , wherein the CD38 antigen binding domain is preceded by a leader nucleotide peptide.
6. The method of claim 1 , wherein the at least one intracellular signaling domain further comprises a CD3 zeta intracellular domain.
7. The method of claim 1 , wherein the nucleic acid sequence encoding the CD38 antigen binding domain comprises a nucleic acid sequence comprising the nucleotide sequence of SEQ ID NO: 5, 7, 9, 21 23, or a sequence with 85%, 90%, 95%, 96%, 97%, 98% or 99% identity thereof.
8. The method of claim 1 , wherein the at least one intracellular signaling domain comprises a costimulatory domain, or a primary signaling domain.
9. The method of claim 8 , wherein the costimulatory domain comprises a functional signaling domain from a protein selected from the group consisting of OX40, CD70, CD27, CD28, CD5, ICAM-1, LFA-1 (CD11a/CD18), ICOS (CD278), DAP10, DAP12, and 4-1BB (CD137).
10. The method of claim 1 , wherein the hematological cancer is multiple myeloma.
11. The method of claim 10 , wherein the hematological cancer is leukemia or lymphoma.
12. The method of claim 11 , wherein the leukemia is acute myeloid leukemia (AML), blastic plasmacytoid dendritic cell neoplasm (BPDCN), chronic myelogenous leukemia (CML), chronic lymphocytic leukemia (CLL), acute lymphoblastic T cell leukemia (T-ALL), or acute lymphoblastic B cell leukemia (B-ALL).
13. The method of claim 11 , wherein the lymphoma is mantle cell lymphoma, non-Hodgkin's lymphoma or Hodgkin's lymphoma.